MECHANISMS OF BRAIN DYSFUNCTION IN TUBEROUS SCLEROSIS

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DESCRIPTION (provided by applicant): Tuberous Sclerosis Complex (TSC) is one of the most common genetic causes of epilepsy. In addition, epilepsy in TSC is typically very severe and intractable to available therapies. Most current treatments for epilepsy are simply symptomatic therapies that may suppress seizures but do not necessarily correct the underlying brain abnormalities causing the epilepsy. Thus, understanding the brain mechanisms causing epilepsy ("epileptogenesis") is necessary to develop more effective, "anti-epileptogenic" treatments for both TSC and non-TSC-related epilepsy. We have previously described a mouse model of TSC that recapitulates many features of human TSC (Tsc1GFAPCKO mice), including severe epilepsy. In the first funding period of this grant, we have described a number of cellular and molecular abnormalities in glia and neurons that contribute to epileptogenesis in these mice, such as astrocyte proliferation, neuronal death, impaired glial buffering of neurotransmitters and potassium ions, and abnormal regulation of specific cell signaling pathways. Most remarkably, we showed that pharmacological inhibition of one of these signaling pathways, the mammalian target of rapamycin (mTOR) pathway, completely prevented the development of epilepsy in Tsc1GFAPCKO mice, representing one of the first demonstrations of a robust anti-epileptogenic effect in any epilepsy model. In this grant renewal application, we propose to extend our previous work, now further characterizing specific TSC-regulated signaling pathways involved in epileptogenesis. Our general hypothesis is that epileptogenesis results primarily from initial abnormalities in specific cell signaling pathways and correction of these signaling abnormalities may prevent epileptogenesis in Tsc1GFAPCKO mice, as well as in other epilepsy models. Findings from this grant should help identify novel mechanisms of epileptogenesis and identify new anti- epileptogenic therapeutic approaches not only for epilepsy in TSC, but potentially for all epilepsy in general.